Lathyrism is a disorder caused by long-term and excessive consumption of the grass pea Lathyrus sativus (Leguminosae). Sometimes other Lathyrus species are involved: L. odoratus, L. cicera, L. ochrus, L. clymenum. The plant is a pulse which is still cultivated in India, Bangladesh, Nepal, Pakistan, Iran, the Middle East, southern Europe, Ethiopia and some places in South America. In India the plant is known as triputa or kesari dhal. Its use is common, in particular in Madhya Pradesh and Bihar. Cases have also been reported from China, Ukraine, Russia, Germany, Syria, Spain, Italy and France. Nowadays most of the problems with lathyrism are limited to India, Bangladesh and Ethiopia.

There are approximately 180 species of the genus Lathyrus. L. sativus can survive at low nutrient levels and grows on various different types of soil, including semi-arid regions with low fertility. In acid soils the farmer needs to add calcium. The plant lives in symbiosis with Rhizobium (nitrogen-fixing bacteria in the root nodules) and in this way adds nitrogen to the soil. In India the plant grows up to 1300 metres above sea level. In Ethiopia it can be cultivated up to 3000 metres above sea level. The yield varies from 900 to 1500 kg per hectare. The plant exhibits important morphologic variations. Osmotic stress increases the concentration of poison.

As early as 400 BC the Indian physician Charak associated eating triputa (L. sativus) with the occurrence of a neurological syndrome. Hippocrates (460-377 BC) wrote that "all men and women who continuously eat peas become impotent in the legs and this situation does not improve". In 1671 the Duke of Wurtemberg passed an edict forbidding the use of L. sativus flour for bread due to its paralytic effects on the legs. In Allahabad, India, attempts were made to prevent cultivation in 1870, but without success. In September 1942, during the Second World War, in a German concentration camp for Rumanian Jews on the Ukrainian border, the flour from this plant was used for daily bread. In December of the same year more than 800 inmates had developed lathyrism. It is estimated that current world production is 12 million tons. The peas are sometimes illegally mixed with the more expensive Cajanus cajan (red gram) and the flour is sometimes illegally mixed with that from Cicer arietinum (Bengal gram). The result is that the earlier epidemic nature of lathyrism has now been replaced by sporadic cases and cases can easily be missed. The plant is sometimes used as cattle fodder. It is chiefly the poor people in the community who exhibit the most severe symptoms. In endemic areas they are sometimes paid in food. At times of famine the plant is a lifesaver; it can after all still ensure a good yield in unfavourable conditions.

It is assumed at present that the poison responsible in the peas is the glutamate analogue beta-(N)-oxalylamino-L-alanine acid (BOAA), also known as beta-N-oxalyl-diamino-propionic acid (beta-ODAP). This neuro-excitatory toxin is a powerful agonist of certain glutamate receptors in the nervous system. Beta-ODAP concentrations vary widely from 0.2 mg to more than 1 mg per gram of seed. If seeds are immersed in water for 24 hours before cooking, the toxin leachs away. However, it is possible that beta-ODAP is not the only poison in the plant.

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The related plant Lathyrus odoratus contains the toxic beta-amino-propionitrile (BAPN). Long-term consumption may lead to skeletal changes. The substance BAPN is an irreversible inhibitor of lysyl oxidase, an enzyme necessary for the covalent cross-linking of tropocollagen molecules during the maturation of mature collagen. A metabolic precursor of BAPN is found in the vegetative parts and unripe seeds of L. sativus. It is probably co-responsible for the osteolathyrism which is sometimes seen after consumption of L. sativus. The role of the related substances dimethylaminopropionitrile (DMAPN) and beta-iminodipropionitrile (IDPN), which are chronic neurotoxins in humans and animals respectively, needs to be further researched.

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A similar toxin, beta-methylamino-L-alanine, is suspected in causing lytico-bodig, a severe neurological disease endemic in Guam, one of the Mariana Islands in the Pacific Ocean.

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Collagen is the name of a family of related molecules. It is the most important fibrous molecule in skin, bone, tendons, cartilage, blood vessels and teeth. In humans we can differentiate between five main types of collagen (types I to V) and a number of minor types. As with other secreted proteins, collagen polypeptides are synthesised in the rough endoplasmic reticulum. The protein chains then pass into the Golgi apparatus, where post-translational modifications take place (chiefly the hydroxylation of proline and lysine side chains). Before secretion, three polypeptide chains combine in the form of a triple spiral. This form is known as procollagen. After excretion into the extracellular space, small extension polypeptides on the N and C terminals of the helix are removed by peptidases, in order to form tropocollagen. The tropocollagen molecules aggregate to microfibrils and are then cross-linked to mature collagen. Tropocollagen is cross-linked, not via sulphur bridges as is the case with many proteins, but via bonds between lysine and its aldehyde derivative allysine. The conversion of lysine to allysine is catalysed by lysyl oxydase. If there is a specific mutation in this enzyme, Ehlers-Danlos syndrome type V develops, resulting in hypermobile joints and hyperelasticity of the skin ("rubber man syndrome"). The same enzyme is inhibited by the BAPN toxin from Lathyrus odoratus, resulting in osteolathyrism.

Almost one third of the amino acid content in collagen consists of the small glycine, while almost one quarter consists of proline. This is very unusual. Every third amino acid is glycine, because it is the only amino acid which is so small that no steric hindrance occurs in the helical structure. The hydroxylated amino acids 4-hydroxyproline and 5-hydroxylysine only occur in collagen. They are formed from their original amino acid by the enzymes proline hydroxylase and lysine hydroxylase respectively. These proteins contain a Fe²⁺ ion at their reaction centre and need ascorbic acid (vitamin C) for their activity. Vitamin C is necessary as an antioxidant to keep iron in its bivalent state. Hydroxyproline is very important for the stability of collagen, in the formation of hydrogen bridges. In vitamin C deficiency, hydroxyproline and hydroxylysine are not produced, which leads to weak collagen fibres, resulting in skin lesions and fragile blood vessels (see Chapter on scurvy).

Animals, chiefly horses, develop paralysis of their hind legs if they are given Lathyrus regularly as fodder. In humans too, there may be problems if these peas are eaten over a prolonged period. Neurolathyrism is characterised by a purely motor hypertonic paresis, in which the legs are affected more than the arms. This is clinically very similar to konzo and to HTLV-1-related tropical spastic paraparesis, but the patient will be seronegative and will not have consumed badly processed bitter cassava (i.e. dietary exposure to cyanide). It is a form of irreversible non-progressive degeneration of the spinal cord. The onset of the symptoms and complaints occur over the course of several weeks, with weakness, stiffness and heaviness of the legs, muscle pain, frequent falls and disturbed gait, micturition problems and sphincter spasms. The signs of motor neuron disorder are pronounced in the lower limbs. Death follows in extreme cases.

The incidence of osteolathyrism in humans is quite poorly documented. Patients develop bone pain and disfigurement of bones, including vertebrae and pelvis. This is to be distinguished from Kashin-Beck's disease.

The diagnosis of neurolathyrism is based on 5 criteria:

• consumption of large amounts of Lathyrus sativus in the weeks prior to the disturbed gait.
• pronounced hypertonic paraparesis
• normal cerebellar tests
• normal feeling and normal cerebral nerves
• no obvious other reason for the paraparesis (cf. Pott’s paralysis, konzo or HTLV-1 infection)

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Evoked somatosensory potentials are normal. There are insufficient anatomopathological data but it is probable that the most important abnormalities are found in the pyramidal system and the motor cortex. In neurolathyrism there is microgliosis in the anterior horn cells and lateral tracts, followed by partial degeneration of the motor pathways of the spinal cord. More research is necessary.

Further consumption of these peas should not be allowed. This is often more easily said than done. The hypertonicity can to a certain extent be controlled by baclofen (Dantrium®, Lioresal®) or tizanidine (Sirdalud®).

There is an international network for the improvement of Lathyrus sativus and the reduction of Lathyrism (INILSEL), with a coordination centre in Pau, France. After identification of beta-ODAP as the toxin, an attempt was made to cultivate toxin-free plants (without beta-ODAP). Since late-onset osteolathyrism has been ascertained in survivors of the above-mentioned concentration camp, 35 years after the event, extreme caution is needed with these "low poison" varieties, because under certain conditions, e.g. unripe seeds, other toxins may be present in the plant. Supplementation of grass pea with food-aid cereals (e.g. at least one third) can be tried to diminish neurolathyrism. Soaking and rinsing seeds before cooking (reduce the availability of the water-soluble neurotoxin) is of doubtfull value in field situations.